The Watanabe heritable hyperlipidemic rabbit (WHHL) provides an experimental animal model for the low density lipoprotein (LDL) receptor defect present in patients homozygous for familial hypercholesterolemia (FH). Both WHHL rabbits and FH patients have a four- to sevenfold increase in plasma levels of apolipoprotein E (apo E). To determine the etiology for the elevated apo E concentrations, kinetic studies of radiolabeled apo E were conducted in WHHL and control New Zealand White (NZW) rabbits. The sites of apo E synthesis in the WHHL rabbit were evaluated by quantitating apo E mRNA levels in 12 tissues by dot-blot analysis of total RNA from each tissue with an apo E cDNA probe. Compared to the NZW rabbit, the WHHL rabbit had a twofold increase in the plasma apo E residence time, a fourfold increase in apo E production rate, and normal apo E mRNA levels in the liver and all other major apo E synthetic tissues. However, a fivefold increase in WHHL aortic apo E mRNA levels was observed. The elevated level of aortic apo E mRNA indicated a potential role for apo E in modulating atherogenesis in the WHHL rabbit. These results established that the increased plasma apo E in the WHHL rabbit was due to increased synthesis and delayed catabolism. Moreover, the fourfold increase in apo E synthesis with normal tissue apo E mRNA levels may reflect a translational or posttranslational regulation of apo E synthesis.